Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells

2005 ◽  
Vol 7 (2) ◽  
pp. 172-178 ◽  
Author(s):  
Carl R. Walkley ◽  
Matthew L. Fero ◽  
Wei-Ming Chien ◽  
Louise E. Purton ◽  
Grant A. McArthur
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Regulators ◽  
Self Renewal ◽  
Haematopoietic Stem Cells ◽  
Negative Cell

scholarly journals Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Nathan Moore ◽  
Stephen Lyle
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Adult Stem Cells ◽  
Cell Populations ◽  
Proliferative Potential ◽  
Cell Cycle Regulators ◽  
Slow Cycling ◽  
Stem Cell Populations

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.

CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development

Oncogene ◽  
2018 ◽  
Vol 38 (14) ◽  
pp. 2580-2594 ◽  
Author(s):  
Yo-Taro Shirai ◽  
Anna Mizutani ◽  
Saori Nishijima ◽  
Masafumi Horie ◽  
Chisato Kikuguchi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Cancer Development ◽  
Cell Cycle Regulators ◽  
Small Cell Lung ◽  
Negative Cell

scholarly journals Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Léonard Hérault ◽  
Mathilde Poplineau ◽  
Adrien Mazuel ◽  
Nadine Platet ◽  
Élisabeth Remy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Regulators ◽  
Potential Mechanism ◽  
Rna Seq ◽  
Hematopoietic Stem ◽  
Age Related ◽  
Undifferentiated State ◽  
Reference Map

Abstract Background Hematopoietic stem cells (HSCs) are the guarantor of the proper functioning of hematopoiesis due to their incredible diversity of potential. During aging, heterogeneity of HSCs changes, contributing to the deterioration of the immune system. In this study, we revisited mouse HSC compartment and its transcriptional plasticity during aging at unicellular scale. Results Through the analysis of 15,000 young and aged transcriptomes, we identified 15 groups of HSCs revealing rare and new specific HSC abilities that change with age. The implantation of new trajectories complemented with the analysis of transcription factor activities pointed consecutive states of HSC differentiation that were delayed by aging and explained the bias in differentiation of older HSCs. Moreover, reassigning cell cycle phases for each HSC clearly highlighted an imbalance of the cell cycle regulators of very immature aged HSCs that may contribute to their accumulation in an undifferentiated state. Conclusions Our results establish a new reference map of HSC differentiation in young and aged mice and reveal a potential mechanism that delays the differentiation of aged HSCs and could promote the emergence of age-related hematologic diseases.

scholarly journals Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells

2012 ◽  
Vol 23 (8) ◽  
pp. 1524-1532 ◽  
Author(s):  
Therese M. Roth ◽  
C.-Y. Ason Chiang ◽  
Mayu Inaba ◽  
Hebao Yuan ◽  
Viktoria Salzmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Germline Stem Cells ◽  
Self Renewal ◽  
Stem Cell Regulation ◽  
Male Germline ◽  
Male Germline Stem Cells ◽  
Nutrient Conditions

Drosophila male germline stem cells (GSCs) divide asymmetrically, balancing self-renewal and differentiation. Although asymmetric stem cell division balances between self-renewal and differentiation, it does not dictate how frequently differentiating cells must be produced. In male GSCs, asymmetric GSC division is achieved by stereotyped positioning of the centrosome with respect to the stem cell niche. Recently we showed that the centrosome orientation checkpoint monitors the correct centrosome orientation to ensure an asymmetric outcome of the GSC division. When GSC centrosomes are not correctly oriented with respect to the niche, GSC cell cycle is arrested/delayed until the correct centrosome orientation is reacquired. Here we show that induction of centrosome misorientation upon culture in poor nutrient conditions mediates slowing of GSC cell proliferation via activation of the centrosome orientation checkpoint. Consistently, inactivation of the centrosome orientation checkpoint leads to lack of cell cycle slowdown even under poor nutrient conditions. We propose that centrosome misorientation serves as a mediator that transduces nutrient information into stem cell proliferation, providing a previously unappreciated mechanism of stem cell regulation in response to nutrient conditions.

Malignant Myeloma Cells Impair Phenotype and Function of stem and Progenitor Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1799-1799
Author(s):  
Ingmar Bruns ◽  
Sebastian Büst ◽  
Akos G. Czibere ◽  
Ron-Patrick Cadeddu ◽  
Ines Brückmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Plasma Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Healthy Donors ◽  
Stem And Progenitor Cells

Abstract Abstract 1799 Poster Board I-825 Multiple myeloma (MM) patients often present with anemia at the time of initial diagnosis. This has so far only attributed to a physically marrow suppression by the invading malignant plasma cells and the overexpression of Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by malignant plasma cells triggering the death of immature erythroblasts. Still the impact of MM on hematopoietic stem cells and their niches is scarcely established. In this study we analyzed highly purified CD34+ hematopoietic stem and progenitor cell subsets from the bone marrow of newly diagnosed MM patients in comparison to normal donors. Quantitative flowcytometric analyses revealed a significant reduction of the megakaryocyte-erythrocyte progenitor (MEP) proportion in MM patients, whereas the percentage of granulocyte-macrophage progenitors (GMP) was significantly increased. Proportions of hematopoietic stem cells (HSC) and myeloid progenitors (CMP) were not significantly altered. We then asked if this is also reflected by clonogenic assays and found a significantly decreased percentage of erythroid precursors (BFU-E and CFU-E). Using Affymetrix HU133 2.0 gene arrays, we compared the gene expression signatures of stem cells and progenitor subsets in MM patients and healthy donors. The most striking findings so far reflect reduced adhesive and migratory potential, impaired self-renewal capacity and disturbed B-cell development in HSC whereas the MEP expression profile reflects decreased in cell cycle activity and enhanced apoptosis. In line we found a decreased expression of the adhesion molecule CD44 and a reduced actin polymerization in MM HSC by immunofluorescence analysis. Accordingly, in vitro adhesion and transwell migration assays showed reduced adhesive and migratory capacities. The impaired self-renewal capacity of MM HSC was functionally corroborated by a significantly decreased long-term culture initiating cell (LTC-IC) frequency in long term culture assays. Cell cycle analyses revealed a significantly larger proportion of MM MEP in G0-phase of the cell cycle. Furthermore, the proportion of apoptotic cells in MM MEP determined by the content of cleaved caspase 3 was increased as compared to MEP from healthy donors. Taken together, our findings indicate an impact of MM on the molecular phenotype and functional properties of stem and progenitor cells. Anemia in MM seems at least partially to originate already at the stem and progenitor level. Disclosures Off Label Use: AML with multikinase inhibitor sorafenib, which is approved by EMEA + FDA for renal cell carcinoma.

A MEIS1 Dependent Genetic Program in Leukemia Associated with Cell Cycle Entry and ‘Stemness’

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 746-746
Author(s):  
Ashish Kumar ◽  
Baolin Wu ◽  
John H. Kersey
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Line ◽  
Fusion Proteins ◽  
Leukemia Cells ◽  
Self Renewal ◽  
Knock Down ◽  
Cell Cycle Entry

Abstract The HOX co-factor MEIS1 is expressed in several leukemias, especially those involving MLL-gene rearrangements. Experimental data have demonstrated that MLL-fusion proteins induce the expression of MEIS1 in hematopoietic cells along with increased self-renewal and recent murine experiments indicate that MEIS1 is central to the growth-promoting effects of MLL fusion proteins. However, the cellular and molecular pathways that are regulated by MEIS1 are unknown. We studied the effect of MEIS1 knock-down in a cell line derived from a leukemic MLL-AF9 knock-in mouse. Transduction of this cell line (4166) with MEIS1-shRNA bearing lentivirus led to significant reduction in MEIS1 expression compared to cells transduced with control virus. The MEIS1 knock-down cells displayed decreased cell cycle entry, while terminal myeloid differentiation and apoptosis were enhanced. To characterize the molecular effects of MEIS1 knock-down, we performed gene expression profiling of leukemia cells with and without MEIS1 expression. We extracted RNA from 5 separate experiments where 4166 cells were transduced with vector control or MEIS1 shRNA for 48 hours and analyzed gene expression profiles using Affymetrix 430 2.0 whole genome arrays. We used a regularized two-sample paired t-test to select genes that were differentially expressed among the two groups. At a false discovery rate (FDR) of ≤ 5%, 1053 probe sets displayed decreased expression with MEIS1 knockdown, while 296 probe sets showed increased expression. Analysis of gene ontology (GO) terms by DAVID (Database for Annotation, Visualization and Integrated Discovery) revealed that the list of genes down-regulated with MEIS1 knock-down was significantly enriched in genes associated with the cell cycle and its regulation (Cdk2, Cdk6, Cdkn3, Ccna2, Cdc7, Cdc42, Rbl1, Wee1) and DNA replication (Brca1, Cdc6, Cdt1, Gmnn, Mcm4, Mcm5, Mcm8). Conversely, the genes displaying increased expression with MEIS1 knockdown were associated with inhibition of proliferation eg. Cdkn1a (p21), Btg2, Btg3 and pro-apoptotic effects such as Bax. A search of the Molecular Signatures Database for previously published profiles that overlap with our list of MEIS1-dependent genes revealed that the profile of MEIS1 knockdown in our murine leukemia cells significantly overlapped with that of neural stem cells. Specifically, of the 1838 genes expressed highly in neural stem cells compared to differentiated brain and bone marrow cells (Ramalho-Santos et al, Science 2002), 155 showed an overlap with the 594 genes in our MEIS1-dependent set (594 gene identifiers contained in 1053 probe sets; p = 3.27 e−28, hypergeometric distribution). This list of 155 genes included MEIS1 and several of the cell cycle and DNA replication-associated genes. These results reveal a core self-renewal genetic program shared by leukemia and neural stem cells that is regulated by MEIS1. Activation of MEIS1 in leukemia and possibly brain tumors could thus enhance self-renewal via the up-regulation of the above common genes. Overall, our results show that MEIS1 regulates cell cycle entry in murine MLL-AF9 leukemia, an effect that enhances self-renewal in other cells as well.

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